0:01Skip to 0 minutes and 1 secondHello. This is Barbara Jennings. Welcome to your tutorial, Cancer Pharmacogenetics. By the end of the session, you'll be able to discuss the use of treatment stratification for cancer patients. Cancer is now viewed as genetic disease and pharmacogenetics is already being applied to its management. Our understanding of the underlying changes is leading to new classification paradigms and individualised treatment protocols for cancer, protocols that are stratified by the results of genetic tests. About half of all the publications about the implementation of genomics in healthcare do concern cancer management. So cancer therapy is fast becoming the poster child for pharmacogenetics. This is an illustration of a carcinogen binding to DNA, and cancer genetics is largely a story of acquired mutations.

1:04Skip to 1 minute and 4 secondsIts pathogenesis is a multi-step process, certainly associated with inherited risk factors, but most importantly with the accumulation of somatic mutations that alter components of key singling pathways- pathways that are important for cell growth, for cell division, and for differentiation. So, the mutations lead to altered protein function, or perhaps protein over-expression, and three

1:34Skip to 1 minute and 34 secondsclasses of genes are mutated: oncogenes, tumor suppressor genes, and those genes that encode DNA repair enzymes. Now mutations arise and accumulate over time through carcinogen exposure, or simply by chance, as cells divide, because much of the pathological process is random - it's marked by heterogeneity. So we see this variation between individuals and tumours of apparently similar or the same histological classification can differ markedly in their genotype. We also know that each tumor will evolve over time, with subtle or marked genetic changes occurring throughout the disease course. Now there is a great deal of scope for the application of genetics to manage risk.

2:27Skip to 2 minutes and 27 secondsIt's a challenge to predict and prevent adverse events when treatments have a very narrow therapeutic index, and this is characteristic of most cancer treatments. Now, if this is the case, it may be particularly critical to understand any predictable pharmacokinetic and pharmacodynamic variants when treating cancer patients. So, to understand those variants that affect the absorption, the distribution, the metabolism, and the excretion of medicines. So, during the rest of this tutorial, we're going to look at three aspects of treatment stratification for cancer. First, there are some examples of rationally designed cancer therapies that target a particular underlying driver mutation. So in these cases an associated biomarkers should be identified through the use of a companion diagnostic test.

3:22Skip to 3 minutes and 22 secondsSecondly, there are these great inter-individual pharmacokinetic differences in response to cytotoxic therapies, and they're associated with significant morbidity and mortality in some cases. We'll briefly explore the utility of genetic tests for adme enzymes and the rationale for dose modification. Finally, and looking to the future, we're going toconsider the place of next-generation sequencing analysis of tumour DNA. So I want to begin by considering three different examples of companion diagnostic tests.

4:00Skip to 4 minutes and 0 secondsNow it can be really important to use biomarker tests to positively identify those patients who will indeed benefit from some rationally designed drugs - so drugs designed against that specific target and a classic example of this type of treatment stratification, is the identification of breast cancer patients whose tumours are said to be HER-2 positive. So that is they over express a protein encoded by the Erb B 2 oncogene and these patients benefit from treatment with a monoclonal antibody therapy directed against this over expressed protein. And so we can see the stratification into two distinct groups of patients - those for whom the reatment will be most beneficial, and those who are negative for the biomarker.

4:52Skip to 4 minutes and 52 secondsNow, another example of this type of treatment stratification can be seen for patients with a subtype of Leukemia - chronic myeloid leukaemia. The leukaemic cells of patients affected by this disease have an underlying mutation called a translocation and it results from the fusion of two oncogene sequences - the BCR oncogene and the C ABL oncogene. And here we see the fusion gene, because labeled B C R and a ABL oncogene probes have been hybridised to a dividing metaphase cell from a patient with chronic myeloid leukaemia. Now the resulting fusion gene expresses a fusion protein and this up regulates a key signaling cascade leading to altered growth and division in the cancer cells.

5:47Skip to 5 minutes and 47 secondsThe altered biochemistry can actually be dampened down with a new drug, imatinib, that was designed to compete with a binding site in the offending fusion protein. Now this class of drug, the first of which was called imatinib, has transformed the outlook for people affected by chronic myeloid leukaemia. Finally, I want to discuss siltuximab which is another designer therapy. This time, an antibody therapy used in head and neck tumours, as well as for lung and colorectal cancers. The antibodies siltuximab and other biological therapies target the surface epidermal growth factor receptor expressed by the EGFR gene, but it's much less effective on tumors harbouring mutations in the KRAS oncogenes, so mutations that affect this protein within this signalling cascade.

6:58Skip to 6 minutes and 58 secondsBecause these mutations will lead to permanent cell singling, so there's a continuous on switch and this will bypass any impact to blocks in the receptors for the EGFR pathway. So the companion diagnostic test for KRAS mutations has a high negative predictive value, confirming the presence of the RAS oncogene mutation will exclude the patient from this form of therapy. I now want to turn my attention to inherited genetic variation that can affect both pharmacokinetics and pharmacodynamics of cancer therapy. There are great inter-individual pharmacokinetic differences in response to cytotoxic therapies and some of these are associated with significant morbidity and mortality.

7:55Skip to 7 minutes and 55 secondsNearly all forms of chemotherapy have a narrow therapeutic index, which is to say that the therapeutic dose is very close to the dose that causes toxicity and some of the adverse events associated with chemo therapies, such as neutropenia and gastrointestinal toxicity are life-threatening. Therefore, biomarkers that can accurately guide individualised dosing could lead to risk mitigation. Pharmacogenetic tests have the potential to make well-established treatment protocols much safer. In considering companion diagnostics we focus on known mutations associated with particular disease sub- classifications. In considering pharmacokinetic and pharmacodynamic tests, we are also constrained by the use of a small number of companion variants that have been studied to date.

8:54Skip to 8 minutes and 54 secondsBut sequencing cancer genomes with no a priori hypotheses opens the possibility of truly individualised therapies and treating cancers according to the patient's background genetics and the tumors perturbed genetic pathways, rather than the appearance of the tumour, the histological subtype of the tumour. Use of whole genome sequencing data, rather thanindividual biomarker tests has become possible through the development of next-generation sequencing strategies, because these are cheap and these are rapid. Now, this approach is also very sensitive and it may lend itself to non-invasive liquid biopsy in the future, and to the monitoring of tumour evolution, so that treatment can be adapted over time for each individual patient.

9:51Skip to 9 minutes and 51 secondsWe can envisage a number of routine uses for the new technologies to improve the tailoring of treatment protocols to the needs of each individual. Tissue biopsy diagnosis will result in the histological classification of each patient's disease as usual but in parallel, DNA extraction can be carried out from the biopsy and from a blood sample and DNA sequencing can be used to identify actionable driver mutations -so mutations for which there may be a companion therapy, and pharmacokinetic, or pharmacodynamic variants. The quality and timing of the subsequent treatment protocol will reflect these findings.

10:42Skip to 10 minutes and 42 secondsFinally, being able to detect circulating tumor DNA in a simple plasma sample which is possible now, could mean that non-invasive liquid biopsies are used to monitor both treatment response and signs of relapse. So treatment product protocols could be modified accordingly without needing expensive invasive and hazardous solid tumor biopsy from the patient. So in summary, genetic tests for underlying somatic mutations that drive carcinogenesis as well as for the variants of enzymes that absorb, distribute, metabolise and excrete drugs are already used in the stratification of cancer treatment, and the availability of cheap and rapid genome sequencing in the future will lead to truly individualised protocols very soon.

Cancer pharmacogenetics tutorial

This tutorial will introduce cancer genetics and describe the translation of research findings into stratified, precision medicine for cancer patients.